Certain scopolammonium compounds

ABSTRACT

WHEREIN R IS A LOWER ALKYL GROUP AND X IS A HALOGEN ATOM. (3-(HO-CH2-CH(-C6H5)-COO-),6,7-(-O-),8-(R-O-(1,4-   PHENYLENE)-),8-(H3C-)-NORTROPANIUM) X(-) 1. SCOPOLAMMONIUM QUATERNARY SALTS REPRESENTED BY THE FORMULA:

United States Patent 3,847,924 CERTAIN SCOPOLAMMONIUM COMPOUNDS Satoru Tanaka and Kazunori Hashimoto, Tokyo, Japan, assignors to Eisai Co., Ltd., Tokyo, Japan No Drawing. Filed May 31, 1973, Ser. No. 365,728 Claims priority, application Japan, June 12, 1972, 47/ 57,633 Int. Cl. C07d 43/ 06 U.S. Cl. 260-292 3 Claims ABSTRACT OF THE DISCLOSURE This invention relates to the new quaternary ammonium salts of scopolamine represented by the formula:

59 O -cH -n-cri II O-C-CH-CH OH wherein R is a lower alkyl group and X is a halogen atom, and a process for the preparation thereof.

scopolamine, atropine and hyoscyamine base are the essential components of the alkaloids contained in belladonna and scopolia. These compounds exhibit a strong parasympathetic blocking activity and they therefore are utilized for the purpose of therapeutical treatment of diseases such as gastric cramp, gastric ulcer, duodenal ulcer and the like. Unfortunately it was found that they show undesirable side effects such as thirst, dysuria, and palpitation and the injurious effects on central nervous system, such as illusion, hemicrania, nausea and the like.

It was found as the result of several researches which had recently been conducted that the aforementioned drawbacks especially the undesired side effects on central nervous system caused by these compounds can considerably be reduced, although their aimed original parasympathetic blocking activity is also somewhat reduced, when these compounds are administrated in a form of their conventional quaternary ammonium salts. The quaternary ammonium salts of atropine such as N-methyl atropinium bromine and N-butyl scopolammonium bromide in the commercial name of Buscopan, for example, are now available in market.

It cannot, however, be pronounced that the side effects on the central nervous system presented by these quaternary ammonium salts was satisfactorily eliminated.

It has now been found according to our extensive researches in this field that the aforementioned drawbacks can satisfactorily be removed by providing the new quaternary ammonium salts which were gained by the reaction of scopolamine base with p-alkoxy-substituted benzyl halide.

The followings are the comparative data with respect to the pharmacological effects and toxicities (as acute toxicity LDso) of N-(p-butoxybenzyl)scopolammonium bromide, hereinafter-called Compound A, as one of the typical quaternary ammonium salts according to the present invention and the hitherto known butyl scopolammonium bromide, herein after called Compound B.

I. Experiment on Isolated Stomach of Rat According to Magnus Method 1. Direct effect:

(a) With 1 10- g./ml. of Compound A, 70.5 percent control of the spontaneous motility was observed.

(b) With 1x10- g./ml. of Compound B, no appreciable control was observed.

2. Blocking effect on the contraction caused by 1 l0 g./ml. of barium chloride:

(a) With 1 10- g./ml. of Compound A, 68.3 percent control of the contraction was observed.

(b) With 1 l0 g./ml. of Compound B, only 15.0

percent control of the contraction was observed.

3. Anti-acetylcholine effect against the contraction caused by 1x10 g./ml. of acetylchloine:

(a) With 1 10-" g./ml. of Compound A, 64.5 percent control of the contraction was observed.

(b) With 1 l0 g./ml. of Compound B, only 15.0

percent control of the contraction was observed.

II. Experiment of the Isolated Small Intestine of Mouse According to Magnus Method 1. Blocking effect on the contraction caused by 5X10 g./ml. of barium chloride:

(a) With 1 l0 g./ml. of Compound A, 32.4 percent control of contraction was observed.

(b) With 1 10- g./ml. of Compound B, only 27.1 percent control was observed.

2. Anti-acetylcholine effect on the contraction caused by 1 10-" g./m1. of acetylcholine:

(a) With l 10- g./ml. of Compound A, 76.8 percent control of the contraction was observed.

(b) With 1X10 g./ml. of Compound B, 15.1 percent control was observed.

III. Acute Toxicity on Male Mouse Weighing ca.

20 Grams Compound A B Subcutaneous injection (LDso), mg./kg 750 580 Oral administration (LDao), mg./kg 2, 200 1, 800

wherein R and X have the same meanings as previously defined with respect to the formula given to the opening paragraph.

Typical solvents which have been found preferable to carry out the above reaction include lower alcohol, acetone, ether, chloroform and the like. The reaction takes place readily at room temperature. In order to avoid the racemisation of the scopolamine compounds, it is advisable to carry out the reaction at a low temperature. The resulting N-(p-loweralkoxybenzyl)scopolammonium bromides are easily soluble in Water. The aqueous solutions thus obtained are stable to heat with no tendency of causing racemisation. The fact olfers one of the serious advantages in the production of pharmaceutical preparations.

The following examples illustrate the invention.

EXAMPLE 1 Preparation of N- (p-methoxybenzyl Scopolamrnonium Bromide To 70 milliliters of a chloroform solution containing 10 grams of scopolamine base were added drop by drop under ice-cooling 3O milliliters of a chloroform solution containing 7 grams of p-methoxybenzyl bromide. After the completion of the addition, the reaction mixture was stirred for one hour under ice-cooling. The stirring was continued for additional one hour at room temperature for carrying out the reaction. After the completion of the reaction, 100 milliliters of isopropyl ether were added to the solution. Crystals which separated out were recovered by filtration. The crystals were recrystallized from chloroform-isopropyl ether to obtain the purposed product in needles which had the melting point of 7580 C. with foaming and decomposition. Yield were 12.8 grams which corresponded to 72.3% of the theory.

Elementary analysis of the product and the calculation for C H BrNO -2H O; Molecular weight 540.46 gave:

To 50 milliliters of a chloroform solution containing 9 grams of scopolamine were added 30 milliliters of a C H N Calculated (percent)- 57. 73 6.92 2. Found (percent) 57.77 6.90 2. 24

Rotatory plarization of the product was:

[a] r 12.6 (c=0.5, l=0.1 in ethanol).

What is claimed is: 1. Scopolammoniurn quaternary salts represented by the formula:

6) wa s-0&

o-ii-cn-cn oa o wherein R is a lower alkyl group and X is a halogen atom.

2. A compound according to claim 1, which is pmethoxybenzyl scopolarnmonium bromide.

3. -A compound according to claim 1, which is pbutoxybenzyl scopolarnmonium bromide.

References Cited UNITED STATES PATENTS 3,696,] 10 10/1972 Tanaka et al 260292 ALAN L. ROTMAN, Primary Examiner US. Cl. X.R. 424265 

1. SCOPOLAMMONIUM QUATERNARY SALTS REPRESENTED BY THE FORMULA: 